CN108178748A - The synthetic method of 4,6- dichloro pyrimidine -5- formonitrile HCNs - Google Patents
The synthetic method of 4,6- dichloro pyrimidine -5- formonitrile HCNs Download PDFInfo
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- CN108178748A CN108178748A CN201810053208.8A CN201810053208A CN108178748A CN 108178748 A CN108178748 A CN 108178748A CN 201810053208 A CN201810053208 A CN 201810053208A CN 108178748 A CN108178748 A CN 108178748A
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- IPEBKIMUIHKZJP-UHFFFAOYSA-N N#Cc(c(Cl)ncn1)c1Cl Chemical compound N#Cc(c(Cl)ncn1)c1Cl IPEBKIMUIHKZJP-UHFFFAOYSA-N 0.000 description 1
- FIABSTHYYTZLPA-UNXLUWIOSA-N Oc1ncnc(O)c1/C=N/O Chemical compound Oc1ncnc(O)c1/C=N/O FIABSTHYYTZLPA-UNXLUWIOSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Abstract
The present invention relates to the synthetic methods of 4,6 dichloro pyrimidine, 5 formonitrile HCN, and in other words, the present invention provides a kind of method for synthesizing 4,6 dichloro pyrimidine of compound, 5 formonitrile HCN, this method reaction condition is mild, environmental protection and intermediate are easy to maintain, convenient for large-scale production.
Description
Technical field
The invention belongs to medicine intermediate fields.More particularly it relates to a kind of synthesis 4,6- dichloro pyrimidines -5-
The method of carbonitrile compounds.
Background technology
4,6- dichloro pyrimidine -5- formonitrile HCNs and its derivative are a kind of important medicine intermediates, can be used for preparing drug,
Such as it can be used for preparing RUP3 receptor antagonists and patent application WO described in patent application WO 2004065380
PI3K kinase inhibitors described in 2015200352 etc..
The synthetic route of compound 4,6- dichloro pyrimidine -5- formonitrile HCNs is by more document reports.For example, patent application
The synthetic method of 4,6- dichloro pyrimidine -5- formonitrile HCNs described in WO2012068343 is former by starting of 4,6- dihydroxy-pyrimidines
Material passes sequentially through Vilsmeier and chlorination, Oximation, dehydration three-step reaction step synthesis target product, closes
It is as shown in Figure 1 into route.The process route there are intermediate thermal stability it is poor, to water sensitive, post processing purification difficult the problems such as,
Therefore large-scale industrial production is not suitable for it.
Invention content
In order to meet compound 4, the requirement of 6- dichloro pyrimidine -5- formonitrile HCN industrial production scales, the present invention provides one
The method of the synthesis compound 4,6- dichloro pyrimidine -5- formonitrile HCNs of kind optimization.This method reaction condition is mild, environmental protection and intermediate are easy
It preserves, is completely suitable for mass producing.
Technical scheme is as follows：
The present invention provides a kind of method for synthesizing compound 4,6- dichloro pyrimidine -5- formonitrile HCNs is (hereinafter referred to as " of the invention
Method "), synthetic route is as shown in Fig. 2, the described method comprises the following steps：
(1) with compound 1
It is raw material with halogenated dehydrated reagent, adds in n,N-Dimethylformamide, it is anti-carries out Vilsmeier in organic solvent
Should, obtain compound 2：
(2) compound 2 is made to be reacted in a solvent with azanol or hydroxylamine hydrochloride, obtains compound 3：
(3) make compound 3 and chloro dehydrated reagent is dehydrated in organic solvent and chlorination, obtain compound 4：
In the method for the invention, in step (1), Vilsmeier well-known to those skilled in the art may be used
The popular response condition of reaction carries out.In some embodiments, the halogenated dehydrated reagent described in step (1) may be selected from trichlorine
Oxygen phosphorus, thionyl chloride, oxalyl chloride, dibromo triphenylphosphine, phosphorus pentachloride or phosgene, preferably phosphorus oxychloride.In the present invention one
In a little embodiments, the organic solvent described in Vilsmeier reactions is halogenated hydrocarbon solvent, preferably dichloromethane.
In the method for the invention, the azanol described in step (2) is preferably hydroxylamine hydrochloride；The solvent for ethyl alcohol,
The mixed solvent of one or both of tetrahydrofuran, acetonitrile or water, preferably second alcohol and water；Reaction temperature is -40-100
DEG C, preferably 10-50 DEG C, more preferably 20-30 DEG C.
In the method for the invention, the chloro dehydrated reagent described in step (3) is phosphorus oxychloride, thionyl chloride, oxalyl
Chlorine, phosphorus pentachloride or phosgene, preferably phosphorus oxychloride；The organic solvent is toluene, acetonitrile, glycol dimethyl ether or 1,
2- dichloroethanes, preferably acetonitrile.
In order to meet compound 4, the requirement of 6- dichloro pyrimidine -5- formonitrile HCN industrial production scales, the present invention provides one
The method of the synthesis compound 4,6- dichloro pyrimidine -5- formonitrile HCNs of kind optimization.This method is in Vilsmeier reactions and chloro dehydration step
The intermediate stablized in rapid, the intermediate are easily isolated purifying, and reaction condition is mild and environmentally friendly；The reaction road of the present invention
Line shares three-step reaction, has good thermal stability, and right without the intermediate of column chromatography purifying generation and the intermediate
Water is stablized, and is easily isolated purifying, can store the long period, be very suitable for large-scale industrial production.
In any structural formula shown in this article, if there is vacant chemical valence on any atom, then the vacant chemical combination
Valency is actually to describe the easy hydrogen atom without specifically describing.
Herein, if giving the title and structural formula of the compound simultaneously for a compound, then two
In the case that person is inconsistent, it is subject to the structure of the compound, unless content based on context can show that the chemical combination provided
The structure of object is incorrect and title is correct.
Specific embodiment
Following embodiments are for example, being understood not to the guarantor limiting the invention in any way to the present invention
Protect range.Disclosed data (for example, amount, temperature etc.) strive ensureing its accuracy, but it is understood that can also exist
Some experimental errors and offset.Unless otherwise stated, the number otherwise in the present invention is parts by weight, and temperature is Celsius temperature,
Pressure is for atmospheric pressure or close to atmospheric pressure.All hydrogen modal datas are measured by Varian 400-MR.All reagents used in the present invention
It is that commercial channel obtains or can be synthesized by one of ordinary skill in the art according to routine techniques.
It is abbreviated list used herein below：
EA ethyl acetate
DIPEA N, N- diisopropylethylamine
THF tetrahydrofurans
DCM dichloromethane
DMF N,N-dimethylformamides
LC-MS liquid chromatography-mass spectrographies
G grams
L liters
Ml milliliters
Mol moles
H hours
Tol toluene
Description of the drawings
Fig. 1 is the synthesis side of compound 4,6- dichloro pyrimidine -5- formonitrile HCNs reported in patent application WO 2012068343
Method with 4,6- dihydroxy-pyrimidines for starting material, passes sequentially through Vilsmeier and chlorination, Oximation, three steps of dehydration is anti-
Target product should have been synthesized.
Fig. 2 is the synthesis compound 4 of the present invention, and it is anti-to pass sequentially through Vilsmeier for the method for 6- dichloro pyrimidine -5- formonitrile HCNs
It answers, Oximation, dehydration chloro three-step reaction have synthesized target product.
Fig. 3 is the TGA measurement charts of the synthetic intermediate 1 of the method for the present invention, example weight 28.548mg, dotted line represent with
10.00 DEG C/min is heated to 300.00 DEG C from 30.00 DEG C, and solid line is shown in 300.00 DEG C of heating 5.0min.Instrument：TGA Q500
V20.10 Build 36, gas 1：Nitrogen, Pan types：Platinum.
Fig. 4 is the TGA measurement charts of the synthetic intermediate 2 of the method for the present invention, example weight 22.326mg, dotted line represent with
10.00 DEG C/min is heated to 300.00 DEG C from 30.00 DEG C, and solid line is shown in 300.00 DEG C of heating 5.0min.Instrument：TGA Q500
V20.10 Build 36, gas 1：Nitrogen, Pan types：Platinum.
Fig. 5 is the high pressure DSC measurement charts of the synthetic intermediate 1 of the method for the present invention, example weight 2.080mg, and dotted line represents
5.0min is heated in 35.00 DEG C.Solid line represents to be heated to 400.00 DEG C from 35.00 DEG C with 5.00 DEG C/min.Module:DSC1/
700/1871, sample container:40 μ l of aluminium standard ware, weight:0, material:Aluminium, method:25-400 10K AL40, dt 1.00s,
35.00 DEG C holding 5.0min, 35.00-400.00 DEG C, 5.00 DEG C/min.
Fig. 6 is the high pressure DSC measurement charts of the synthetic intermediate 2 of the method for the present invention, example weight 1.450mg, and dotted line represents
5.0min is heated in 35.00 DEG C.Solid line represents to be heated to 400.00 DEG C from 35.00 DEG C with 5.00 DEG C/min.Module:DSC1/
700/1871, sample container:40 μ l of aluminium standard ware, weight:0, material:Aluminium, method:25-400 10K AL40, dt 1.00s,
35.00 DEG C holding 5.0min, 35.00-400.00 DEG C, 5.00 DEG C/min.
Fig. 7 is the TGA measurement charts of the synthetic intermediate 1 of 2012068343 methods of patent application WO, example weight
9.3390mg.Method：Ramp, 10.00 DEG C/min are heated to 300.00 DEG C from 10.00 DEG C, instrument：TGA Q500 V20.10
Build 36, gas 1：Nitrogen, Pan types：Platinum.
Fig. 8 is the TGA measurement charts of the synthetic intermediate 2 of 2012068343 methods of patent application WO, example weight
8.4850mg.Method：Ramp, 10.00 DEG C/min are heated to 300.00 DEG C from 10.00 DEG C, instrument：TGA Q500 V20.10
Build 36, gas 1：Nitrogen, Pan types：Platinum.
Fig. 9 is the high pressure DSC measurement charts of the synthetic intermediate 1 of 2012068343 methods of patent application WO, example weight
4.3600mg.Module:DSC1/700/1871, sample container:40 μ l of aluminium standard ware, weight:0, material:Aluminium, method:25-
400 10K AL40, dt 1.00s, [1] 25.0..400.0 DEG C, 10.00K/min, N2 50.0ml/min.
Figure 10 is the high pressure DSC measurement charts of the synthetic intermediate 2 of 2012068343 methods of patent application WO, example weight
5.1600mg.Module:DSC1/700/1871, sample container:40 μ l of aluminium standard ware, weight:0, material:Aluminium, method:25-
400 10K AL40, dt 1.00s, [1] 25.0..400.0 DEG C, 10.00K/min, N2 50.0ml/min.
Embodiment 1
The synthesis of N- ((4,6- dihydroxy-pyrimidine -5- bases) methylene)-N- methyl first ammonium villaumites
DCM (600ml) and POCl is sequentially added in reaction bulb3(80ml, 862mmol), stirs evenly, and is passed through nitrogen guarantor
Shield is cooled to 5-10 DEG C, and the solution that DMF (66.04ml, 856mmol) is dissolved in DCM (200ml) is added dropwise, is stirred after dropwise addition
15-20min, is warming up to 25-30 DEG C, after stirring 1-2 hours, added in into reaction solution 4,6- dihydroxy-pyrimidines (80g,
714mmol), it reacts 22 hours, filters at 25-30 DEG C, filter cake is washed twice with DCM (150ml), drained, at 40-45 DEG C
Vacuum drying, obtains 139.4g yellow solids, is target compound.
1H NMR (400MHz, DMSO) δ 9.03 (s, 1H), 8.47-8.40 (m, 1H), 3.62 (d, J=0.8Hz, 3H),
3.30 (d, J=0.9Hz, 3H)
LC-MS:[M]+:168
Embodiment 2
The synthesis of 4,6- dihydroxy-pyrimidine -5- formaldoximes
Method one
Hydroxylamine hydrochloride (122.85g, 1.768mol), water (240ml) and ethyl alcohol (1200ml), solution are added in into reaction bulb
After clarification, N- ((4,6- dihydroxy-pyrimidine -5- bases) methylene)-N- methyl first ammonium villaumites (120g, 0.589mol) are added portionwise,
Then it is reacted 17 hours at 20-30 DEG C.Filtering, obtained filter cake is washed twice with ethyl alcohol (240ml), then at 40-45 DEG C
Vacuum drying, obtains 89.4g products, is target compound.
1H NMR(400MHz,DMSO)δ11.45(s,1H),8.83(s,1H),8.32(s,1H)..
LC-MS:[M+H]+:156
Method two
Hydroxylamine hydrochloride (6.14g, 88.40mmol), water (36ml) are sequentially added in reaction bulb, stirring is warming up to 20-30
DEG C, be added portionwise at this temperature N- ((4,6- dihydroxy-pyrimidine -5- bases) methylene)-N- methyl first ammoniums villaumite (6.0g,
29.47mmol), a batch, every batch of about 1g are added at interval of 10-15min.20-30 DEG C is reacted 17 hours, filtering, filter cake nothing
Water-ethanol (12ml) washes twice, and drains, and 40-45 DEG C of vacuum drying obtains 3.89g yellow solids, is target compound.
1H NMR(400MHz,DMSO)δ11.45(s,1H),8.83(s,1H),8.32(s,1H).
LC-MS:[M+H]+:156
Method three
Water (30ml) is added in reaction bulb to stir, and is warming up to 20-30 DEG C, ((4,6- dihydroxy are phonetic by 20-30 DEG C of addition N-
Pyridine -5- bases) methylene)-N- methyl first ammonium villaumites (10.0g, 49.11mmol), 20-30 DEG C is reacted 18 hours, is added in reaction solution
Enter 50ml absolute ethyl alcohols, stir, filtering, filter cake is washed with a small amount of absolute ethyl alcohol, drained, and 40-45 DEG C of vacuum drying obtains
5.77g yellow solid.
1H NMR(400MHz,DMSO)δ9.83(s,1H),8.74(s,1H).
LC-MS:[M+H]+:141
Hydroxylamine hydrochloride (2.98g, 42.83mmol), absolute ethyl alcohol (20ml) are sequentially added in reaction bulb, water (5ml) stirs
It mixes, is warming up to 20-30 DEG C, add in 4,6- dihydroxy-pyrimidine -5- formaldehyde (2.0g, 14.28mmol), 20-30 DEG C of reaction 18 is small
When, filtering, filter cake is washed with a small amount of absolute ethyl alcohol, drained, and 40-45 DEG C is dried in vacuo to obtain 2.28g yellow solids, is targeted
Close object.
1H NMR(400MHz,DMSO)δ11.58(s,3H),8.78(s,1H),8.31(s,1H).
LC-MS:[M+H]+:156
Embodiment 3
The synthesis of 4,6- dihydroxy-pyrimidine -5- formonitrile HCNs
POCl is sequentially added into reaction bulb3(5ml, 53.65mmol), 4,6- dihydroxy-pyrimidine -5- formaldoximes (1.0g,
8.92mmol), stir, be warming up to 80-90 DEG C and react 2 hours, sequentially add toluene and acetonitrile after cooling, rotate it is near dry, to anti-
It answers and methanol (4ml) is added in bottle, stir, filtering, filter cake is washed with a small amount of methanol, drained, and obtains 0.323g yellow solids, is mesh
Mark compound.
1H NMR (400MHz, DMSO) δ 12.76 (s, 2H), 8.81 (s, 1H)
13C NMR (400MHz, DMSO) δ 161.66,151.86,117.03,75.87
LC-MS:[M+H]+:138
Embodiment 4
The synthesis of 4,6- dichloro pyrimidine -5- formonitrile HCNs
Acetonitrile (850ml) and POCl are added in into reaction bulb3(254.60ml, 2.732mol), at 20-30 DEG C, drop
Add DIPEA (377.68ml, 2.278mol), after being added dropwise to complete, be added portionwise 4,6- dihydroxy-pyrimidine -5- formaldoximes (85g,
0.548mol), it after adding, after being warming up to 80-85 DEG C of reaction 3 hours, is concentrated under reduced pressure, and concentrate is added dropwise to water (1.7L)
In be quenched, product is precipitated from water.The filter cake being obtained by filtration washes the wet product that twice, obtains with water (170ml) with EA (1080ml)
At 45-50 DEG C with activated carbon decolorizing after dissolving, after the filtrate that is obtained by filtration is concentrated and dried, with the mixed solvent system of EA and DCM
Slurry, the filter cake being obtained by filtration decompression drying at 45-50 DEG C obtain 45.3g solids, are target compound.
1H NMR(400MHz,CDCl3)δ8.95(s,1H).
13C NMR(100MHz,CDCl3)δ164.28,159.36,111.12,111.03.
GC-MS:[M]+:173。
The intermediate obtained in synthetic method of the present invention and the intermediate in the method for patent application WO 2012068343
Stability experiment.
By in high pressure DSC and TGA data method more of the invention and the method for patent application WO2012068343
The stability of mesosome, is as a result given in the table below,
Two intermediates in synthetic method of the present invention it can be seen from result in above-mentioned table and figure are relative to WO
2012068343 two intermediates show very excellent stability, exothermic phenomenon do not occur, also without spontaneous combustion and quick-fried
Fried risk occurs.Intermediate 2 in synthetic method of the present invention just occurs drastically putting only in up to 160.19 DEG C or more of temperature
Heat and spontaneous combustion or risk of explosion.
Claims (12)
1. synthesizing compound 4, the method for 6- dichloro pyrimidine -5- formonitrile HCNs the described method comprises the following steps：
(1) with compound 1
It is raw material with halogenated dehydrated reagent, adds in n,N-Dimethylformamide, carries out Vilsmeier reactions in organic solvent,
Obtain compound 2：
(2) compound 2 is made to be reacted in a solvent with azanol, obtains compound 3：
(3) make compound 3 and chloro dehydrated reagent is dehydrated in organic solvent and chlorination, obtain compound 4：
2. synthesis compound 4 according to claim 1, the method for 6- dichloro pyrimidine -5- formonitrile HCNs, it is characterised in that step
(1) the halogenated dehydrated reagent described in is trifluoromethanesulfanhydride anhydride, acetic anhydride, phosphorus oxychloride, thionyl chloride, oxalyl chloride, dibromo three
Phenylphosphine, phosphorus pentachloride or phosgene.
3. synthesis compound 4 according to claim 1, the method for 6- dichloro pyrimidine -5- formonitrile HCNs, it is characterised in that step
(1) organic solvent described in is halogenated hydrocarbons.
4. synthesis compound 4 according to claim 3, the method for 6- dichloro pyrimidine -5- formonitrile HCNs, it is characterised in that described
Halogenated hydrocarbons is dichloromethane.
5. the synthesis compound 4 according to any one of claim 1-4, the method for 6- dichloro pyrimidine -5- formonitrile HCNs is special
Sign is that the azanol described in step (2) is hydroxylamine hydrochloride.
6. the synthesis compound 4 according to any one of claim 1-4, the method for 6- dichloro pyrimidine -5- formonitrile HCNs is special
Sign is that the solvent in step (2) is one or both of ethyl alcohol, tetrahydrofuran, acetonitrile or water.
7. synthesis compound 4 according to claim 6, the method for 6- dichloro pyrimidine -5- formonitrile HCNs, it is characterised in that step
(2) solvent described in is the mixed solvent of second alcohol and water.
8. the synthesis compound 4 described in any one of claim 1-4, the method for 6- dichloro pyrimidine -5- formonitrile HCNs, feature exist
Reaction temperature in step (2) is -40-100 DEG C.
9. synthesis compound 4 according to any one of claims 8, the method for 6- dichloro pyrimidine -5- formonitrile HCNs, it is characterised in that in step (2)
Reaction temperature be 10-50 DEG C.
10. synthesis compound 4 according to any one of claims 8, the method for 6- dichloro pyrimidine -5- formonitrile HCNs, it is characterised in that in step (2)
Reaction temperature be 20-30 DEG C.
11. the synthesis compound 4 according to any one of claim 1-4, the method for 6- dichloro pyrimidine -5- formonitrile HCNs is special
Sign is that the chloro dehydrated reagent described in step (3) is phosphorus oxychloride, thionyl chloride, oxalyl chloride, phosphorus pentachloride or phosgene.
12. the synthesis compound 4 according to any one of claim 1-4, the method for 6- dichloro pyrimidine -5- formonitrile HCNs is special
Sign is that the organic solvent wherein described in step (3) is toluene, acetonitrile, glycol dimethyl ether or 1,2- dichloroethanes.
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| JP2002145866A (en) * | 2000-11-06 | 2002-05-22 | Fuji Photo Film Co Ltd | Method for producing imidazole compound and imidazomalononitrile compound |
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| CN1823056A (en) * | 2003-07-11 | 2006-08-23 | 艾尼纳制药公司 | Trisubstituted aryl and heteroaryl derivatives as modulatorsof metabolism and the prophylaxis and treatment of disorders related thereto |
| US20070111992A1 (en) * | 2005-09-23 | 2007-05-17 | N.V. Organon | 4-Phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives |
| WO2012096061A1 (en) * | 2011-01-14 | 2012-07-19 | 株式会社エス・ディー・エス バイオテック | Pyrimidine-derived pest-control agent for use in agriculture and horticulture |
| CN103524423A (en) * | 2013-09-18 | 2014-01-22 | 苏州乔纳森新材料科技有限公司 | Preparation method of 4,6-dichloropyrimidine-5-acetaldehyde |
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2018
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|---|---|---|---|---|
| CN1528751A (en) * | 1994-04-26 | 2004-09-15 | Process for preparing 4,6-dichloropyrimidine | |
| JP2002145866A (en) * | 2000-11-06 | 2002-05-22 | Fuji Photo Film Co Ltd | Method for producing imidazole compound and imidazomalononitrile compound |
| CN1823056A (en) * | 2003-07-11 | 2006-08-23 | 艾尼纳制药公司 | Trisubstituted aryl and heteroaryl derivatives as modulatorsof metabolism and the prophylaxis and treatment of disorders related thereto |
| US20070111992A1 (en) * | 2005-09-23 | 2007-05-17 | N.V. Organon | 4-Phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives |
| WO2012096061A1 (en) * | 2011-01-14 | 2012-07-19 | 株式会社エス・ディー・エス バイオテック | Pyrimidine-derived pest-control agent for use in agriculture and horticulture |
| CN103524423A (en) * | 2013-09-18 | 2014-01-22 | 苏州乔纳森新材料科技有限公司 | Preparation method of 4,6-dichloropyrimidine-5-acetaldehyde |
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